Diffuse Lewy body disease is a distinct neuropathological entity that occurs in a pure form, pDLBD, or in association with other dementing and neurodegenerative disorders like Alzheimer disease and progressive supranuclear palsy, aDLBD. Clinically this disorder is associated with progressive dementia, extrapyramidal signs and not uncommonly with psychiatric symptoms. The disorder is being increasingly recognized in neuropathologic practice and is by some authorities believed to be the second most common dementing disorder. The underlying disease mechanism is unknown, although the characteristic hallmark of the disease, the presence of cortical Lewy Bodies, appears to be preferentially localized to neocortical, limbic, and subcortical projection areas of the ventral tegmental dopamine system. These changes are accompanied by dystrophic neuritic change in the same areas. As previously demonstrated by this laboratory, these abnormalities are associated with profound neuronal loss of the ventro-medial pigmented nuclei of the substantia nigra complex, as well as a moderate loss of cholinergic neurons of the nucleus basalis of Meynert (nbM). In this proposal we wish to test the hypothesis that DLBD is a dying back phenomenon of the ventral tegmental dopamine system, which projects to the cerebral cortex and limbic areas with rostral to caudal anatomic gradient of decreasing density. To test this hypothesis we propose to examine the temporal and spatial occurrence of histopathological abnormalities using quantitative morphometric techniques combined with extensive light microscopic and ultrastructural immunocytochemical methodologies. The temporal occurrence of dystrophic changes in terminal dopaminergic axons and cell somata, deafferentiation of the target neurons in the projection ares, the presence of subsequent transsynaptic occurrence of Lewy bodies, and cell death in the nuclei of origin in the ventral tegmental nuclei will be reconstructed by comparing the quantity of the various structural abnormalities in a number of locations along the spatial gradient. The sequence of postsynaptic events will be approached by comparing the extent of postsynaptic receptor loss, assessed by autoradiographic binding assays, with immunocytochemical abnormalities and the occurrence and composition of lewry bodies in the targeted neurons. The significance of the abnormalities affecting the cholinergic basal forebrain system in pDLBD and DLBD associated with AD will be examined by correlating the quantitative pathology with quantitative psychological and cognitive tests performed by the Clinical Core of the MADRC ante-mortem. We anticipate examine 15 cases each of pDLBD, DLBD/AD, and normal age-matched controls.